TY - JOUR
T1 - Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival
AU - Medraño-Fernandez, Iria
AU - Bestetti, Stefano
AU - Bertolotti, Milena
AU - Bienert, Gerd P.
AU - Bottino, Cinzia
AU - Laforenza, Umberto
AU - Rubartelli, Anna
AU - Sitia, Roberto
N1 - Publisher Copyright:
© 2016, Mary Ann Liebert, Inc.
PY - 2016/6/20
Y1 - 2016/6/20
N2 - Aquaporin-8 (AQP8) allows the bidirectional transport of water and hydrogen peroxide across biological membranes. Depending on its concentration, H2O2 exerts opposite roles, amplifying growth factor signaling in physiological conditions, but causing severe cell damage when in excess. Thus, H2O2 permeability is likely to be tightly controlled in living cells. Aims: In this study, we investigated whether and how the transport of H2O2 through plasma membrane AQP8 is regulated, particularly during cell stress. Results: We show that diverse cellular stress conditions, including heat, hypoxia, and ER stress, reversibly inhibit the permeability of AQP8 to H2O2 and water. Preventing the accumulation of intracellular reactive oxygen species (ROS) during stress counteracts AQP8 blockade. Once inhibition is established, AQP8-dependent transport can be rescued by reducing agents. Neither H2O2 nor water transport is impaired in stressed cells expressing a mutant AQP8, in which cysteine 53 had been replaced by serine. Cells expressing this mutant are more resistant to stress-, drug-, and radiation-induced growth arrest and death. Innovation and Conclusion: The control of AQP8-mediated H2O2 transport provides a novel mechanism to regulate cell signaling and survival during stress.
AB - Aquaporin-8 (AQP8) allows the bidirectional transport of water and hydrogen peroxide across biological membranes. Depending on its concentration, H2O2 exerts opposite roles, amplifying growth factor signaling in physiological conditions, but causing severe cell damage when in excess. Thus, H2O2 permeability is likely to be tightly controlled in living cells. Aims: In this study, we investigated whether and how the transport of H2O2 through plasma membrane AQP8 is regulated, particularly during cell stress. Results: We show that diverse cellular stress conditions, including heat, hypoxia, and ER stress, reversibly inhibit the permeability of AQP8 to H2O2 and water. Preventing the accumulation of intracellular reactive oxygen species (ROS) during stress counteracts AQP8 blockade. Once inhibition is established, AQP8-dependent transport can be rescued by reducing agents. Neither H2O2 nor water transport is impaired in stressed cells expressing a mutant AQP8, in which cysteine 53 had been replaced by serine. Cells expressing this mutant are more resistant to stress-, drug-, and radiation-induced growth arrest and death. Innovation and Conclusion: The control of AQP8-mediated H2O2 transport provides a novel mechanism to regulate cell signaling and survival during stress.
UR - http://www.scopus.com/inward/record.url?scp=84975832591&partnerID=8YFLogxK
U2 - 10.1089/ars.2016.6636
DO - 10.1089/ars.2016.6636
M3 - Article
C2 - 26972385
AN - SCOPUS:84975832591
SN - 1523-0864
VL - 24
SP - 1031
EP - 1044
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 18
ER -